1. Field of the Invention
The present invention relates generally to the fields of molecular biology, immunology, and medicine. More particularly, it concerns epitopes of TCL1 that are recognized by T cells and may be used to treat a cancer.
2. Description of Related Art
Malignancies of B-cell origin are typically responsive to combination chemotherapy and complete remissions can be induced in many patients; nonetheless, relapse continues to be a significant clinical problem. The use of rituximab, an anti-CD20 monoclonal antibody in combination with chemotherapy has improved the overall and complete response rates, progression-free survival, overall survival, and curability of patients with B-cell non-Hodgkin's lymphomas (Marcus et al., 2005; Cheson and Leonard; Coiffier et al., 2002). However, relapse remains a significant cause of treatment failure and novel treatments are needed to eradicate minimal residual disease to further improve clinical outcome in these patients.
While immunotherapy with idiotype vaccines may offer promise for treatment of B-cell malignancies, identification of novel lymphoma-associated antigens that are widely expressed is necessary to overcome the barriers of patient-specific idiotype vaccines. Therapeutic agents used to eradicate minimal residual disease should ideally be directed at different targets and have different mechanisms of action than agents used in induction therapy. They should also be safe with minimal adverse effects since they may need to be administered as maintenance therapy over several months. Therapeutic vaccines may provide many of these desirable features as they can target different antigens on the lymphoma tumor cells than those targeted by rituximab or chemotherapy agents, and they have been observed to be safe and well tolerated (Houot and Levy, 2009; Park and Neelapu, 2008). Furthermore, by inducing immunological memory and polyclonal humoral and cellular immune responses, vaccines may potentially produce a sustained antitumor effect, and unlike monoclonal antibodies, they may prevent the emergence of antigen-loss variants. Thus, therapeutic vaccines against lymphomas can be complementary to passive immunotherapeutic agents such as monoclonal antibodies and cytotoxic chemotherapeutic agents and could be ideal for eradicating minimal residual disease.
Several groups have used the clonal tumor immunoglobulin expressed on the surface of mature B-cell malignancies, termed idiotype, as a tumor-specific antigen for development of therapeutic vaccines against lymphomas (Di Nocola et al., 2009; Timmerman et al., 2002; Navarrete et al., 2011; Bertinetti et al., 2006; Inoges et al., 2006; Neelapu et al., 2005; Malyguine et al., 2004; Bendandi et al., 1999; Kwak et al., 1992). Idiotype vaccines were shown to be safe and induced sustained antitumor antibody and CD4+ and CD8+ T-cell responses in patients with follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL) (Di Nocola et al., 2009; Timmerman et al., 2002; Navarrete et al., 2011; Bertinetti et al., 2006; Inoges et al., 2006; Neelapu et al., 2005; Malyguine et al., 2004; Bendandi et al., 1999; Kwak et al., 1992). Furthermore, idiotype vaccines induced molecular remissions when administered after standard chemotherapy (Bendandi et al., 1999). A recently completed randomized, double blind, multicenter phase III clinical trial showed that idiotype vaccination improves disease-free survival when administered in the setting of minimal residual disease in FL, providing proof of principle that therapeutic vaccines can improve clinical outcome in these patients (Schuster et al., 2011). However, a major limitation of idiotype vaccines is the requirement for a custom-made product for each patient that makes the manufacturing of the vaccine expensive, laborious, and time-consuming. To overcome these difficulties, there is a clear need for the identification of novel lymphoma-associated antigens that are shared between patients and widely expressed in multiple B-cell malignancies.